Mechanisms of age-related inflammatory response in hemorrhagic shock

失血性休克年龄相关炎症反应机制

基本信息

批准号：
7483099
负责人：
BASILIA ZINGARELLI
金额：
$ 30.14万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483099
关键词：
2,4-thiazolidinedione 9-deoxy-delta-9-prostaglandin D2 Adult Age Age-Months Aging-Related Process Anti-Inflammatory Agents Anti-inflammatory Apoptotic Cardiovascular system Cell Adhesion Molecules Cells Cessation of life Childhood Clinical Condition Dependency Development Down-Regulation Endothelial Cells Event Exhibits Functional disorder Hemorrhage Hemorrhagic Shock Incidence Inflammation Inflammatory Inflammatory Response Injury Intensive Care Units Intercellular adhesion molecule 1 Intervention Leukocytes Ligands Liquid substance Liver Lung Mediating Mediator of activation protein Metabolic Mitogen-Activated Protein Kinase 3 Modification Molecular Multiple Organ Failure Neutrophil Infiltration Nuclear Nuclear Receptors Nutritional Support Organ Oxidative Stress Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Physiological Physiological reperfusion Population Process Production Prostaglandins Protein Kinase Proteins RNA Interference Rattus Regulation Reperfusion Therapy Research Personnel Resuscitation Role Secondary to Severities Shock Signal Transduction Small Interfering RNA Small RNA Syndrome Testing Thiazolidinediones Tissues Trauma age related chemokine ciglitazone clinically relevant cyclopentenone gain of function hemodynamics in vivo in vivo Model juvenile animal kinase inhibitor loss of function lung injury macrophage migration monocyte neutrophil novel therapeutics pediatric trauma programs research study trafficking transcription factor upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The clinical scenario of trauma and severe hemorrhage is characterized by an overwhelming activation of several inflammatory mediators and by modification of the interactions between leukocytes and endothelial cells, leading to sequestration of neutrophils into the tissues and organs. Clinical observations suggest that pediatric trauma victims have lower incidence of multiple organ dysfunction syndrome (MODS) than adult patients. However, the precise molecular mechanisms are not clear. In preliminary in vivo studies we have found that under physiological conditions, lung expression of the peroxisome proliferator activated receptor-y PARY), a nuclear receptor with putative anti-inflammatory role, is a function of the aging process and is maximally expressed at young age, while it declines in mature rats. This age-dependent decline of PPARy expression inversely correlates with phosporylation of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinases known to be capable of modifying PPARy activity. We also have found that mature rats, when subjected to hemorrhagic shock, exhibit a more pronounced lung and liver injury when compared with young rats. Our hypothesis is that the severity of the systemic inflammatory response during hemorrhagic shock is age-dependent and is modulated at the nuclear level by a diverse regulation of the PPARy pathway. Three interrelated specific aims will test this hypothesis. (1) We will define the age-dependency of the PPARy pathway during the aging process under normal physiological conditions and after hemorrhagic shock in vivo. (2) With "gain-of-function" and "loss-of-function" studies, we will evaluate the precise role of the PPARy pathway on the systemic inflammatory response during hemorrhagic shock in vivo in young and mature rats. (3) We will identify the molecular mechanisms of the age-dependent dysregulation of PPARy by evaluating the role of the upstream regulatory kinases ERK1/2. A common clinical observation in intensive care units is that pediatric patients are less susceptible to develop multiple organ dysfunction syndrome and recover relatively uneventfully than adult trauma victims. Our project is aimed to identify the molecular mechanisms responsible of the diverse inflammatory response in the adult and the pediatric patients, and will provide valuable information for the developing of novel therapeutic approaches for the treatment of trauma and hemorrhage.

描述（由申请人提供）：创伤和严重出血的临床情况的特征是几种炎症介质的压倒性激活以及白细胞和内皮细胞之间相互作用的改变，导致中性粒细胞被隔离到组织和器官中。临床观察表明，儿童创伤受害者的多器官功能障碍综合征（MODS）发生率低于成年患者。然而，确切的分子机制尚不清楚。在初步的体内研究中，我们发现在生理条件下，过氧化物酶体增殖物激活受体-y PARY（一种具有假定抗炎作用的核受体）的肺部表达是衰老过程的一个功能，并且在年轻时表达最多，而在成熟大鼠中则下降。 PPARγ 表达的这种年龄依赖性下降与细胞外信号调节激酶 1 和 2 (ERK 1/2) 的磷酸化呈负相关，这些蛋白激酶已知能够改变 PPARγ 活性。我们还发现，与年轻大鼠相比，成熟大鼠在遭受失血性休克时表现出更明显的肺和肝损伤。我们的假设是失血性休克期间全身炎症反应的严重程度与年龄有关，并且在核水平上受到 PPARγ 途径的多种调节的调节。三个相互关联的具体目标将检验这一假设。 (1)我们将定义正常生理条件下和体内失血性休克后衰老过程中PPARγ途径的年龄依赖性。 (2)通过“功能获得”和“功能丧失”研究，我们将评估PPARγ通路对年轻和成年大鼠体内失血性休克期间全身炎症反应的精确作用。 (3)我们将通过评估上游调节激酶ERK1/2的作用来确定年龄依赖性PPARγ失调的分子机制。重症监护病房的一个常见临床观察结果是，与成人创伤受害者相比，儿科患者不易患多器官功能障碍综合征，并且恢复相对顺利。我们的项目旨在确定成人和儿童患者多种炎症反应的分子机制，并将为开发治疗创伤和出血的新型治疗方法提供有价值的信息。